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Synthesis, Quantification and NMR Characterization of Bioactive Compounds

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Analytical Chemistry".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 28702

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Prof. Dr. Pierangela Ciuffreda

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Department of Biomedical and Clinical Sciences “L. Sacco”, University of Milan, Milano, Italy
Interests: synthesis; quantification and NMR characterization of bioactive compounds such as steroids; glycosides and nucleotides; applications of biocatalysis in water and organic solvents to the synthesis of compounds of biopharmaceutical interest including modified nucleosides; design; synthesis and biological characterization of nucleoside analogues as antitumoral agents; ongoing projects regard either the synthesis; biological characterization; and quantification in biological matrices of endocannabinoids and N-acylethanolamides or the synthesis; biological characterization of FAAH and MAGL inhibitors

Prof. Dr. Diego Colombo

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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy
Interests: main research interests encompass mainly bioorganic chemistry and nuclear magnetic resonance applied to molecular modelling for structure-activity relationships of biologically important molecules, as an example, several compounds inspired to natural glycoglycerolipids obtained by chemical and chemoenzymatic procedures, have been studied as potential cancer chemo-preventive substances basing on their antitumor-promoting activity both in vitro and in vivo models; more recently synthetic analogues of natural anionic glycolipids such as sulfoquinovosyldiacylglycerols (SQDG) and glucuronosyldiacylglycerol (GlcADG) whose structure is intriguingly related to the bioactive phosphatidylinositols, have been proposed as Protein Kinase B (Akt) inhibitors and assayed for their anti-proliferative activity in some human cancer cell lines

Special Issue Information

Dear Colleagues,

The term “bioactive compound” simply defines a substance that has a biological activity. As the name suggests (the Greek bios refers to life, and the Latin activus means “dynamic, or full of energy, or involving an activity”), a bioactive compound has the ability to interact with one or more components of the living tissue. These compounds have a wide range of effects. Some definitions bind the bioactivity just for the positive effects in the body that may promote good health. In this way, bioactivity can be beneficial for humans. Nevertheless, researching different bioactive effects (including the "negative" effects) for human benefit was always, and will remain, a large area of the scientist research, not only in terms of health, but also in various fields, such as agriculture, industry, or cosmetics aspiring to improve the quality of human life at the end.

The origin of these substances can be natural, from plants, fruit, vegetables, animals or from other living organisms such as microorganisms, bacteria, and fungi. Examples of these include lycopene, resveratrol, flavonoids, anthocyanins, tannins, betalains, and carotenoids.

However, thanks to the development of pharmaceutical chemistry and new tools for chemical synthesis, it has made it possible to add a synthetic source, either partially or in total.

In this regard, clarifying the structure of bioactive compounds, both natural and synthetic, is a fundamental objective of research in this field and NMR spectroscopy has proven to be a powerful tool.

Finally, quantification of bioactive compounds in plants, fruit, vegetables, or other living organisms is essential for their possible application not only as a preventive role for human health but also for understanding, for example, of their nutraceutical potential and future application in the food industry.

Author contributions, whether in the form of original research or review articles, covering all aspects of both natural and/or synthetic "bioactive compounds," applied not only to human health but also to agrochemicals, cosmetics, food industry, nano-bio-science, etc., are topics of concern for this Special Issue.

Prof. Dr. Pierangela Ciuffreda
Prof. Dr. Diego Colombo
Guest Editors

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Keywords

bioactive compounds
Bioactive properties
NMR
chemical composition and quantity

Published Papers (9 papers)

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Research

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18 pages, 4731 KiB

Open AccessArticle

Direct Quantitation of Phytocannabinoids by One-Dimensional ¹H qNMR and Two-Dimensional ¹H-¹H COSY qNMR in Complex Natural Mixtures

by Evangelos Dadiotis, Vangelis Mitsis, Eleni Melliou and Prokopios Magiatis

Molecules 2022, 27(9), 2965; https://doi.org/10.3390/molecules27092965 - 05 May 2022

Cited by 5 | Viewed by 2670

Abstract

The widespread use of phytocannabinoids or cannabis extracts as ingredients in numerous types of products, in combination with the legal restrictions on THC content, has created a need for the development of new, rapid, and universal analytical methods for their quantitation that ideally could be applied without separation and standards. Based on previously described qNMR studies, we developed an expanded ¹H qNMR method and a novel 2D-COSY qNMR method for the rapid quantitation of ten major phytocannabinoids in cannabis plant extracts and cannabis-based products. The ¹H qNMR method was successfully developed for the quantitation of cannabidiol (CBD), cannabidiolic acid (CBDA), cannabinol (CBN), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabigerol (CBG), cannabigerolic acid (CBGA), Δ9-tetrahydrocannabinol (Δ9-THC), Δ9-tetrahydrocannabinolic acid (Δ9-THCA), Δ8-tetrahydrocannabinol (Δ8-THC), cannabielsoin (CBE), and cannabidivarin (CBDV). Moreover, cannabidivarinic acid (CBDVA) and Δ9-tetrahydrocannabivarinic acid (Δ9-THCVA) can be distinguished from CBDA and Δ9-THCA respectively, while cannabigerovarin (CBGV) and Δ8-tetrahydrocannabivarin (Δ8-THCV) present the same ¹H-spectra as CBG and Δ8-THC, respectively. The COSY qNMR method was applied for the quantitation of CBD, CBDA, CBN, CBG/CBGA, and THC/THCA. The two methods were applied for the analysis of hemp plants; cannabis extracts; edible cannabis medium-chain triglycerides (MCT); and hemp seed oils and cosmetic products with cannabinoids. The ¹H-NMR method does not require the use of reference compounds, and it requires only a short time for analysis. However, complex extracts in ¹H-NMR may have a lot of signals, and quantitation with this method is often hampered by peak overlap, with 2D NMR providing a solution to this obstacle. The most important advantage of the COSY NMR quantitation method was the determination of the legality of cannabis plants, extracts, and edible oils based on their THC/THCA content, particularly in the cases of some samples for which the determination of THC/THCA content by ¹H qNMR was not feasible. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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16 pages, 1528 KiB

Open AccessArticle

Clarifying the Use of Benzylidene Protecting Group for D-(+)-Ribono-1,4-Lactone, an Essential Building Block in the Synthesis of C-Nucleosides

by Silvana Casati, Paola Rota, Pietro Allevi, Alessandra Mingione, Roberta Ottria and Pierangela Ciuffreda

Molecules 2021, 26(21), 6447; https://doi.org/10.3390/molecules26216447 - 26 Oct 2021

Cited by 2 | Viewed by 1734

Abstract

In the last two years, nucleosides analogues, a class of well-established bioactive compounds, have been the subject of renewed interest from the scientific community thanks to their antiviral activity. The COVID-19 global pandemic, indeed, spread light on the antiviral drug Remdesivir, an adenine C-nucleoside analogue. This new attention of the medical community on Remdesivir prompts the medicinal chemists to investigate once again C-nucleosides. One of the essential building blocks to synthetize these compounds is the D-(+)-ribono-1,4-lactone, but some mechanistic aspects linked to the use of different carbohydrate protecting groups remain unclear. Here, we present our investigations on the use of benzylidene as a ribonolactone protecting group useful in the synthesis of C-purine nucleosides analogues. A detailed 1D and 2D NMR structural study of the obtained compounds under different reaction conditions is presented. In addition, a molecular modeling study at the B3LYP/6-31G* level of theory with the SM8 solvation model for CHCl₃ and DMSO to support the obtained results is used. This study allows for clarifying mechanistic aspects as the side reactions and structural rearrangements liked to the use of the benzylidene protecting group. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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17 pages, 2437 KiB

Open AccessArticle

Reconstitution of Caveolin-1 into Artificial Lipid Membrane: Characterization by Transmission Electron Microscopy and Solid-State Nuclear Magnetic Resonance

by Yanli Zhang, Xinyan Zhang, Wenru Kong and Shuqi Wang

Molecules 2021, 26(20), 6201; https://doi.org/10.3390/molecules26206201 - 14 Oct 2021

Cited by 4 | Viewed by 1993

Abstract

Caveolin-1 (CAV1), a membrane protein that is necessary for the formation and maintenance of caveolae, is a promising drug target for the therapy of various diseases, such as cancer, diabetes, and liver fibrosis. The biology and pathology of caveolae have been widely investigated; however, very little information about the structural features of full-length CAV1 is available, as well as its biophysical role in reshaping the cellular membrane. Here, we established a method, with high reliability and reproducibility, for the expression and purification of CAV1. Amyloid-like properties of CAV1 and its C-terminal peptide CAV1(168-178) suggest a structural basis for the short linear CAV1 assemblies that have been recently observed in caveolin polyhedral cages in Escherichia coli (E. coli). Reconstitution of CAV1 into artificial lipid membranes induces a caveolae-like membrane curvature. Structural characterization of CAV1 in the membrane by solid-state nuclear magnetic resonance (ssNMR) indicate that it is largely α-helical, with very little β-sheet content. Its scaffolding domain adopts a α-helical structure as identified by chemical shift analysis of threonine (Thr). Taken together, an in vitro model was developed for the CAV1 structural study, which will further provide meaningful evidences for the design and screening of bioactive compounds targeting CAV1. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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20 pages, 2780 KiB

Open AccessArticle

Investigating the Disordered and Membrane-Active Peptide A-Cage-C Using Conformational Ensembles

by Olena Dobrovolska, Øyvind Strømland, Ørjan Sele Handegård, Martin Jakubec, Morten L. Govasli, Åge Aleksander Skjevik, Nils Åge Frøystein, Knut Teigen and Øyvind Halskau

Molecules 2021, 26(12), 3607; https://doi.org/10.3390/molecules26123607 - 12 Jun 2021

Viewed by 2132

Abstract

The driving forces and conformational pathways leading to amphitropic protein-membrane binding and in some cases also to protein misfolding and aggregation is the subject of intensive research. In this study, a chimeric polypeptide, A-Cage-C, derived from α-Lactalbumin is investigated with the aim of elucidating conformational changes promoting interaction with bilayers. From previous studies, it is known that A-Cage-C causes membrane leakages associated with the sporadic formation of amorphous aggregates on solid-supported bilayers. Here we express and purify double-labelled A-Cage-C and prepare partially deuterated bicelles as a membrane mimicking system. We investigate A-Cage-C in the presence and absence of these bicelles at non-binding (pH 7.0) and binding (pH 4.5) conditions. Using in silico analyses, NMR, conformational clustering, and Molecular Dynamics, we provide tentative insights into the conformations of bound and unbound A-Cage-C. The conformation of each state is dynamic and samples a large amount of overlapping conformational space. We identify one of the clusters as likely representing the binding conformation and conclude tentatively that the unfolding around the central W23 segment and its reorientation may be necessary for full intercalation at binding conditions (pH 4.5). We also see evidence for an overall elongation of A-Cage-C in the presence of model bilayers. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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16 pages, 6055 KiB

Open AccessArticle

Resolving Entangled J_H-H-Coupling Patterns for Steroidal Structure Determinations by NMR Spectroscopy

by Danni Wu, Kathleen Joyce Carillo, Jiun-Jie Shie, Steve S.-F. Yu and Der-Lii M. Tzou

Molecules 2021, 26(9), 2643; https://doi.org/10.3390/molecules26092643 - 30 Apr 2021

Cited by 1 | Viewed by 2758

Abstract

For decades, high-resolution ¹H NMR spectroscopy has been routinely utilized to analyze both naturally occurring steroid hormones and synthetic steroids, which play important roles in regulating physiological functions in humans. Because the ¹H signals are inevitably superimposed and entangled with various J_H–H splitting patterns, such that the individual ¹H chemical shift and associated J_H–H coupling identities are hardly resolved. Given this, applications of thess information for elucidating steroidal molecular structures and steroid/ligand interactions at the atomic level were largely restricted. To overcome, we devoted to unraveling the entangled J_H–H splitting patterns of two similar steroidal compounds having fully unsaturated protons, i.e., androstanolone and epiandrosterone (denoted as 1 and 2, respectively), in which only hydroxyl and ketone substituents attached to C3 and C17 were interchanged. Here we demonstrated that the J_H–H values deduced from 1 and 2 are universal and applicable to other steroids, such as testosterone, 3β, 21-dihydroxygregna-5-en-20-one, prednisolone, and estradiol. On the other hand, the ¹H chemical shifts may deviate substantially from sample to sample. In this communication, we propose a simple but novel scheme for resolving the complicate J_H–H splitting patterns and ¹H chemical shifts, aiming for steroidal structure determinations. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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11 pages, 3702 KiB

Open AccessArticle

Matrix-Assisted DOSY for Analysis of Indole Alkaloid Mixtures

by Yu-Lin You, Fei-Fei Li, Ning Wang and Shu-Qi Wang

Molecules 2021, 26(6), 1751; https://doi.org/10.3390/molecules26061751 - 20 Mar 2021

Cited by 2 | Viewed by 2919

Abstract

Diffusion-ordered spectroscopy (DOSY) is a powerful tool for investigating mixtures and identifying peaks of chemical components. However, similar diffusion coefficients of the components, particularly for complex mixtures that contain crowded resonances, limit resolution and restrict application of the DOSY technique. In this paper, matrix-assisted DOSY were used to explore whether the diffusion resolution of a complex model involving indole alkaloid mixtures can be realized. Furthermore, we investigated the influence of different factors on the separation effect. The results showed that the changes in diffusion coefficient differences were achieved more obviously when using sodium dodecyl sulfate (SDS) micelles as the matrix. In addition, we also found that increasing the concentration of SDS can improve the resolution of the DOSY spectrum. Finally, after investigating the influence factors and NMR conditions, we demonstrated the applications of the SDS-assisted DOSY on analyzing the total alkaloid extract of Alstonia Mairei, and the virtual separation of mixtures was achieved. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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15 pages, 1568 KiB

Open AccessArticle

Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds

by Silvia Panzeri, Daniela Arosio, Silvia Gazzola, Laura Belvisi, Monica Civera, Donatella Potenza, Francesca Vasile, Isabell Kemker, Thomas Ertl, Norbert Sewald, Oliver Reiser and Umberto Piarulli

Molecules 2020, 25(24), 5966; https://doi.org/10.3390/molecules25245966 - 16 Dec 2020

Cited by 5 | Viewed by 3593

Abstract

Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso-Asp-Gly- Arg (isoDGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one isoDGR cyclic peptidomimetics containing (1S,2R) and (1R,2S) cis-2-amino-1-cyclopentanecarboxylic acid (cis-β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified α_vβ₃ and α₅β₁ receptors using biotinylated vitronectin (α_vβ₃) and fibronectin (α₅β₁) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for α_vβ₃ over α₅β₁. In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin α_vβ₃). The two RGD ligands showed IC₅₀ values in the same micromolar range as the reference compound (cyclo[RGDfV]), while for the isoDGR derivative an IC₅₀ value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and isoDGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the α_Vβ₃ integrin active site, provided a rationale for the behavior of these ligands toward the receptor. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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Review

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17 pages, 4697 KiB

Open AccessReview

Research Progress of NMR in Natural Product Quantification

by Zhi-Fan Wang, Yu-Lin You, Fei-Fei Li, Wen-Ru Kong and Shu-Qi Wang

Molecules 2021, 26(20), 6308; https://doi.org/10.3390/molecules26206308 - 19 Oct 2021

Cited by 23 | Viewed by 5453

Abstract

In the fields of medicine and health, traditional high-performance liquid chromatography or UV-visible spectrophotometry is generally used for substance quantification. However, over time, nuclear magnetic resonance spectroscopy (NMR) has gradually become more mature. Nuclear magnetic resonance spectroscopy has certain advantages in the quantitative analysis of substances, such as being nondestructive, having a high flux and short analysis time. Nuclear magnetic resonance spectroscopy has been included in the pharmacopoeiae of various countries. In this paper, the principle of nuclear magnetic resonance spectroscopy and the recent progress in the quantitative study of natural products by NMR are reviewed, and its application in the quantitative study of natural products is proposed. At the same time, the problems of using NMR alone to quantify natural products are summarized and corresponding suggestions are put forward. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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13 pages, 990 KiB

Open AccessReview

Synthesis, Quantification, and Characterization of Fatty Acid Amides from In Vitro and In Vivo Sources

by Ruidong Ni, Suzeeta Bhandari, Perry R. Mitchell, Jr., Gabriela Suarez, Neel B. Patel, Kara Lamb, Kirpal S. Bisht and David J. Merkler

Molecules 2021, 26(9), 2543; https://doi.org/10.3390/molecules26092543 - 27 Apr 2021

Cited by 2 | Viewed by 4067

Abstract

Fatty acid amides are a diverse family of underappreciated, biologically occurring lipids. Herein, the methods for the chemical synthesis and subsequent characterization of specific members of the fatty acid amide family are described. The synthetically prepared fatty acid amides and those obtained commercially are used as standards for the characterization and quantification of the fatty acid amides produced by biological systems, a fatty acid amidome. The fatty acid amidomes from mouse N₁₈TG₂ cells, sheep choroid plexus cells, Drosophila melanogaster, Bombyx mori, Apis mellifera, and Tribolium castaneum are presented. Full article

(This article belongs to the Special Issue Synthesis, Quantification and NMR Characterization of Bioactive Compounds)

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